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Mesenchymal stem cells promote liver regeneration and prolong survival in small-for-size liver grafts: involvement of C-Jun N-terminal kinase, cyclin D1, and NF-κB.

Wang W, Du Z, Yan J, Ma D, Shi M, Zhang M, Peng C, Li H - PLoS ONE (2014)

Bottom Line: MSCs were successfully induced into hepatocyte-like cells, osteoblasts and adipocytes in vitro.Increased activities of AP-1 and NF-κB, as well as elevated expressions of p-c-Jun, cyclin D1, and proliferating cell nuclear antigen (PCNA), were also found in MSCs therapy group.These data suggest that MSCs therapy promotes hepatocyte proliferation and prolongs survival in SFSLT by reducing ischemia reperfusion injury and acute inflammation, and sustaining early increased expressions of c-Jun N-terminal Kinase, Cyclin D1, and NF-κB.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Department of Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou University School of Medicine, Zhengzhou, Henan Province, China.

ABSTRACT

Background: The therapeutic potential of mesenchymal stem cells (MSCs) has been highlighted recently for treatment of acute or chronic liver injury, by possibly differentiating into hepatocyte-like cells, reducing inflammation, and enhancing tissue repair. Despite recent progress, exact mechanisms of action are not clearly elucidated. In this study, we attempted to explore whether and how MSCs protected hepatocytes and stimulated allograft regeneration in small-for-size liver transplantation (SFSLT).

Methods: SFSLT model was established with a 30% partial liver transplantation (30PLT) in rats. The differentiation potential and characteristics of bone marrow derived MSCs were explored in vitro. MSCs were infused transvenously immediately after graft implantation in therapy group. Expressions of apoptosis-, inflammatory-, anti-inflammatory-, and growth factor-related genes were measured by RT-PCR, activities of transcription factors AP-1 and NF-κB were analyzed by EMSA, and proliferative responses of the hepatic graft were evaluated by immunohistochemistry and western blot.

Results: MSCs were successfully induced into hepatocyte-like cells, osteoblasts and adipocytes in vitro. MSCs therapy could not only alleviate ischemia reperfusion injury and acute inflammation to promote liver regeneration, but also profoundly improve one week survival rate. It markedly up-regulated the mRNA expressions of HGF, Bcl-2, Bcl-XL, IL-6, IL-10, IP-10, and CXCR2, however, down-regulated TNF-α. Increased activities of AP-1 and NF-κB, as well as elevated expressions of p-c-Jun, cyclin D1, and proliferating cell nuclear antigen (PCNA), were also found in MSCs therapy group.

Conclusion: These data suggest that MSCs therapy promotes hepatocyte proliferation and prolongs survival in SFSLT by reducing ischemia reperfusion injury and acute inflammation, and sustaining early increased expressions of c-Jun N-terminal Kinase, Cyclin D1, and NF-κB.

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Mesenchymal stem cell (MSC) culture and identification.(A) The morphology of MSCs cultured at 5th, 7th, and 11st day (magnification ×100); (B) Fluorescence-activated cell sorting analysis of rat MSCs. Numbers in the panels represent percentage of the cells expressing each marker.
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pone-0112532-g001: Mesenchymal stem cell (MSC) culture and identification.(A) The morphology of MSCs cultured at 5th, 7th, and 11st day (magnification ×100); (B) Fluorescence-activated cell sorting analysis of rat MSCs. Numbers in the panels represent percentage of the cells expressing each marker.

Mentions: MSCs were generated by standard procedures and grown for at least three passages in culture. Contaminating hemotopoietic cells were depleted during passaging, and MSCs were morphologically defined by a fibroblast-like appearance and their identity was confirmed by flow cytometry (Fig 1). Over 95% of the isolated MSCs expressed CD29 and CD90, but not CD34 or CD45. These results are in accordance with well-established markers of bone marrow-derived MSCs.


Mesenchymal stem cells promote liver regeneration and prolong survival in small-for-size liver grafts: involvement of C-Jun N-terminal kinase, cyclin D1, and NF-κB.

Wang W, Du Z, Yan J, Ma D, Shi M, Zhang M, Peng C, Li H - PLoS ONE (2014)

Mesenchymal stem cell (MSC) culture and identification.(A) The morphology of MSCs cultured at 5th, 7th, and 11st day (magnification ×100); (B) Fluorescence-activated cell sorting analysis of rat MSCs. Numbers in the panels represent percentage of the cells expressing each marker.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4257551&req=5

pone-0112532-g001: Mesenchymal stem cell (MSC) culture and identification.(A) The morphology of MSCs cultured at 5th, 7th, and 11st day (magnification ×100); (B) Fluorescence-activated cell sorting analysis of rat MSCs. Numbers in the panels represent percentage of the cells expressing each marker.
Mentions: MSCs were generated by standard procedures and grown for at least three passages in culture. Contaminating hemotopoietic cells were depleted during passaging, and MSCs were morphologically defined by a fibroblast-like appearance and their identity was confirmed by flow cytometry (Fig 1). Over 95% of the isolated MSCs expressed CD29 and CD90, but not CD34 or CD45. These results are in accordance with well-established markers of bone marrow-derived MSCs.

Bottom Line: MSCs were successfully induced into hepatocyte-like cells, osteoblasts and adipocytes in vitro.Increased activities of AP-1 and NF-κB, as well as elevated expressions of p-c-Jun, cyclin D1, and proliferating cell nuclear antigen (PCNA), were also found in MSCs therapy group.These data suggest that MSCs therapy promotes hepatocyte proliferation and prolongs survival in SFSLT by reducing ischemia reperfusion injury and acute inflammation, and sustaining early increased expressions of c-Jun N-terminal Kinase, Cyclin D1, and NF-κB.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Department of Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou University School of Medicine, Zhengzhou, Henan Province, China.

ABSTRACT

Background: The therapeutic potential of mesenchymal stem cells (MSCs) has been highlighted recently for treatment of acute or chronic liver injury, by possibly differentiating into hepatocyte-like cells, reducing inflammation, and enhancing tissue repair. Despite recent progress, exact mechanisms of action are not clearly elucidated. In this study, we attempted to explore whether and how MSCs protected hepatocytes and stimulated allograft regeneration in small-for-size liver transplantation (SFSLT).

Methods: SFSLT model was established with a 30% partial liver transplantation (30PLT) in rats. The differentiation potential and characteristics of bone marrow derived MSCs were explored in vitro. MSCs were infused transvenously immediately after graft implantation in therapy group. Expressions of apoptosis-, inflammatory-, anti-inflammatory-, and growth factor-related genes were measured by RT-PCR, activities of transcription factors AP-1 and NF-κB were analyzed by EMSA, and proliferative responses of the hepatic graft were evaluated by immunohistochemistry and western blot.

Results: MSCs were successfully induced into hepatocyte-like cells, osteoblasts and adipocytes in vitro. MSCs therapy could not only alleviate ischemia reperfusion injury and acute inflammation to promote liver regeneration, but also profoundly improve one week survival rate. It markedly up-regulated the mRNA expressions of HGF, Bcl-2, Bcl-XL, IL-6, IL-10, IP-10, and CXCR2, however, down-regulated TNF-α. Increased activities of AP-1 and NF-κB, as well as elevated expressions of p-c-Jun, cyclin D1, and proliferating cell nuclear antigen (PCNA), were also found in MSCs therapy group.

Conclusion: These data suggest that MSCs therapy promotes hepatocyte proliferation and prolongs survival in SFSLT by reducing ischemia reperfusion injury and acute inflammation, and sustaining early increased expressions of c-Jun N-terminal Kinase, Cyclin D1, and NF-κB.

Show MeSH
Related in: MedlinePlus